DE102008058514A1 - Screening device for estimation/prediction of e.g. solubility characteristics, of pharmaceutical substance in pharmaceutical industry, has distribution/mixing mechanism that is formed and dimensioned to immerse in release volumes - Google Patents

Abstract

The device has a release tank i.e. basket, forming release volumes that accommodate a compound sample and a release medium. The volumes are circularly arranged around an axis. A distribution/mixing mechanism is attached to the release volumes for distribution/mixing of the medium within the release volumes. The release volumes exhibit a size ranging from 5 to 30 ml. The mechanism is formed and dimensioned to immerse in the release volumes. The release volumes are formed by recesses introduced in a central retention device. An independent claim is also included for a method for finding a formulation by analysis of release behaviors of sample of compound.

Description

The The invention relates to a device for the prejudgment of properties of compositions, in particular a pre-evaluation screening device of solubility properties, in vitro properties as well Preliminary assessment / prediction of in vivo properties of Compositions comprising at least one, a composition sample and release medium receiving release volume and at least a device associated with the respective release volume for distribution / mixing within the release volume.

The The invention further relates to a method for formulation finding by analyzing the release behavior of samples of compositions.

Under A composition according to the invention is a substance or Mixture understood, these in different state forms may be present. Substances and / or mixtures may be included in the gaseous state, for example in the form of an aerosol, in the liquid state, in particular as a suspension, in the solid state Condition, in particular as a tablet, granules or powder or semi-solid Condition, in particular pasty state, present. In the pharmaceutical Range includes this as a descriptive drug Formulation of at least one active ingredient in a given temporal behavior must be released.

Under Release is the release of an active substance and / or the solution behavior understood in a release medium.

The Provision of medicines takes place in a form which the desired bioavailability guaranteed. These Form is also referred to as formulation, which as a composition can exist in different state forms. In the development such formulations require a great deal of experimentation to determine an optimal composition and dosage form, in particular when the active ingredient contained in the composition is heavy soluble or only slightly permeable and therefore complex Adjuvant admixtures are required to ensure adequate bioavailability to ensure. To get the most accurate forecast the drug behavior, in particular the release behavior of the respective active ingredient in a formulation already relatively early be able to meet, so-called release attempts carried out in standardized release equipment. In these, the active ingredient of the formulation according to a Dose in a buffer of physiological pH and under sink conditions released at 37 ° C with stirring. The release devices can be constructed in different ways. The basic principle is the introduction of a composition sample in a release volume, the introduction preferably in a release medium contained in the release volume Mixing / distribution with / in this takes place. This is the simplest If at least one such release volume is arranged in a receiving device, in which the stirrer is submersible. In general, will be Release media contained predefined release volumes from 500 ml to 1,000 ml, more rarely up to 4,000 ml. These condition a correspondingly large amount of active ingredient in a composition sample and a higher outlay for deployment the same experimental conditions, for example a corresponding one predefined constant temperature. Problematic the fact that on the one hand either only small amounts of active ingredient available for these experiments or the required experimental materials are very expensive, so that the whole process of formulation finding very elaborate and costly designed. The device described is expanding the large release volumes are very large and is therefore more difficult to handle. Accordingly, a cleaning very elaborate and awkward.

Devices for the release of substances and for the analysis of the release behavior are described by way of example in the following documents. From the publication US 5,639,974 a release device is previously known, which comprises a receiving device for at least one release vessel, said release vessel is adapted to receive a predefined amount of a release medium can. A drive head is opposite, preferably arranged above the receiving device and mounted relative to this movable between an upper and a lower position on a frame. At least one stirring device is attached to the drive head, wherein the individual stirrer is arranged and aligned such that it dips into the release vessel in the lower position of the drive head, while in the upper position a distance between the individual stirrer and the receiving device is provided. In the coupling between the drive and the individual devices, a braking device is provided for the purpose of setting the speed. Such devices are used in the above-mentioned orders of magnitude, which are characterized by a very large amount of material for the provision of the composition samples. Further developments of such a release apparatus are from the documents US Pat. No. 6,558,957 B1 and US 6,174,497 B1 previously known. These disclosed devices are arranged in series release volume.

There are a number of possibilities with regard to the design of the device for mixing / distribution. As a rule, so-called stirring devices are used, ie arranged on a rotatable shaft and rotatably mounted active elements. It is also conceivable to ensure the distribution by the rotating movement of a container receiving the composition sample. An embodiment in the form of such Körbchenrührers is from the US 3,572,648 previously known.

To adjust the sampling to the filling volume, it is off EP 0 779 506 previously known to perform an automatically controlled height adjustment of stirring device and means for sampling in the form of samplers.

For in-situ measurement according to US 6,558,957 such as WO 01/55698 and US 6,174,497 Fiber optic probes are used, which can be arranged in the shaft of a stirrer device and thus allow a turbulence-free measurement.

To full automation can be done according to US 4,879,917 an opening is provided in the bottom of the release volume, and the device is automatically emptied, cleaned and restarted.

Out US 6,060,024 For example, an automated release device with integrated nozzle is previously known as a flushing device for the purpose of cleaning.

Out the product sheets "μdiss-small volume dissolution profiler "of the company Pion is a release device already known in a compact design, in which the device designed for mixing / distribution as a magnetic body is. However, this carries the risk of destroying solid formulation samples through mechanical stress. A transferability of this Execution on the standard executions is in This form does not exist and the measurement of the properties characterizing actual values takes place exclusively via Fiber optic probes.

The known devices are usually larger Release volume characterized, which increased one Material used for the composition samples, a longer one Duration of the experiment and increased control technology Effort to keep the boundary conditions constant. The construction method is space intensive and accordingly the handling, in particular complicated during the trials and for cleaning.

Of the Invention is therefore the object of a method and a Device of the type mentioned in such a way, that the mentioned disadvantages are avoided and in particular with less material used to provide a large number of composition samples a very fast and compared to the prior art comparable meaningful Assessment of the release behavior of this is possible.

The solution according to the invention is characterized by the features of claims 1 and 46 characterized. Advantageous embodiments are described in the subclaims.

A Inventive device for preliminary assessment properties of compositions, in particular screening device for the preliminary assessment of solubility properties, in vitro properties as well as pre-assessment / prediction of in vivo properties of compositions, in particular a pre-evaluation screening device of properties of formulation proposals Compositions comprising at least one, the composition receiving release volume and at least one, the respective Release volume associated with mixing / distribution device composition and / or compositional components released with release medium contained in the release volume is characterized in that that the size of the single release volume in the range of> 0 ml ≤ 100 ml, preferably between and including 5 ml and 50 ml, more preferably between inclusive 5 ml and 30 ml, most preferably between 5 ml and 20 ml and the device for mixing / distribution designed and dimensioned such that they are suitable is to be immersed in the release volume.

Under A release volume in the sense of the invention becomes a deliverable and a volume descriptive volume understood, which of a wall is at least partially limited. That as a cavity present volume serves to accommodate the composition. By the Provide a, the cavity at least partially enclosing Wall, this is by a geometric shape, in particular one describable three-dimensional body, with the wall through at least one opening is characterized, that of the supply the composition and / or the deduction of at least partially released Composition samples are used.

As properties to be assessed in the context of the invention are essentially, the bioavailability characterizing properties of these substances and / or mixtures when used to assess formulation suggestions in phar and the solution behavior of these descriptive quantities. Essential properties are understood to be the release behavior and the precipitation behavior of constituents of substances, in particular of active substances. Substances are substances which cause a specific reaction in an organism in a predefined dose. These can be incorporated with adjuvants which are added to the composition, for example in the form of a carrier substance for the active ingredient.

The Device according to the invention allows in a particularly advantageous manner, the assessment of the release behavior of compositions with a minimum cost of materials to achieve comparable Results within the limits of a permissible tolerance band defined release equipment with larger Release volume for formulation suggestions descriptive compositions in the development of pharmaceutical Substances according to the prior art. In the Dependence of the available release volume amount of material to be assessed in a composition sample and thus the material requirement for a set of composition samples for formulation suggestions can be relatively low held in advance with low material use the Composition of a formulation proposal with regard to can be determined and optimized to be achieved properties. The device according to the invention allows thus, a method for preselecting formulation proposals, which are formed by compositions corresponding to the for these determined properties when selecting another Procedure for accurate assessment can be subjected.

• – Vorgabe zumindest eines Sollwertes zumindest einer vordefinierten Eigenschaft, insbesondere Eigenschaft einer Zusammensetzung, vorzugsweise Ausmaß und Zeitpunkt der Löslichkeit über die Zeit (Löslichkeitsprofil),;
• – Durchführen von Freisetzungsversuchen mit Proben von Zusammensetzungen in vordefinierten, Freisetzungsmedien enthaltenden Freisetzungsvolumen mit einer Größe im Bereich von > 0 ml ≤ 100 ml, bevorzugt zwischen einschließlich 5 ml und 50 ml, besonders bevorzugt zwischen einschließlich 5 ml und 30 ml, ganz besonders bevorzugt zwischen 5 ml und 20 ml unter Bestimmung von Istwerten der vordefinierter Eigenschaften der Zusammensetzungen, wobei die Menge/Größe der einzelnen Probe als Funktion des jeweils zur Verfügung stehenden Freisetzungsvolumens gewählt ist;
• – Einstufung der Proben der Zusammensetzungen in Abhängigkeit der Istwerte als „mögliche geeignete Zusammensetzungen” oder Verwerfen als „ungeeignete Zusammensetzungen”
• – Durchführung von Freisetzungsversuchen mit Proben von als „mögliche geeignete Zusammensetzungen” eingestuften Zusammensetzungen in Freisetzungsmedien enthaltenden Freisetzungsvolumen mit einer Größe von > 200 ml bis 5000 ml, bevorzugt 200 ml bis 2000 ml, besonders bevorzugt zwischen 500 ml und 1000 ml unter Bestimmung der Istwerte der vordefinierten Eigenschaften;
• – Ermittlung der geeigneten Zusammensetzungen als Formulierung in Abhängigkeit der Istwerte.

The formulation finding method according to the invention by analysis of the release behavior of samples of compositions is two-stage and characterized essentially by the following features:

• - Specification of at least one setpoint value of at least one predefined property, in particular property of a composition, preferably extent and time of solubility over time (solubility profile);
• Performing release experiments with samples of compositions in predefined release volume containing release media having a size in the range of> 0 ml ≤ 100 ml, preferably between 5 ml and 50 ml inclusive, more preferably between 5 ml and 30 ml, most preferably between 5 ml and 20 ml, determining actual values of the predefined properties of the compositions, the amount / size of the individual sample being chosen as a function of the respective available release volume;
• - Classification of the samples of the compositions as a function of the actual values as "possible suitable compositions" or discarding as "unsuitable compositions"
• Carrying out release experiments with samples of compositions classified as "possible suitable compositions" in release media containing a size of> 200 ml to 5000 ml, preferably 200 ml to 2000 ml, particularly preferably between 500 ml and 1000 ml, determining the actual values of predefined properties;
• - Determination of the appropriate compositions as a formulation depending on the actual values.

there takes place according to the invention Method in a device according to the invention for the preliminary assessment of solubility properties, in vitro properties as well as pre-assessment / prediction of in vivo properties of compositions, a sample addition to a plurality of release volumes, in which the device for mixing / distribution, in particular Stirrer, are submersible. According to the chosen Experimental parameters such as stirring speed, stirring time, Media type (buffer type, strength or pH) and temperature the sampling takes place after a predefined period of time, which is an evaluation regarding the solubility profile (Dissolution rate, solubility and precipitation behavior) and from this the potential bioavailability in case of Application in vivo of such executed compositions allows. Based on this preselection can unfavorable formulation suggestions in advance be excluded, with classified in a corresponding pre-selection Formulation suggestions in another procedural section may be subjected to a further subsequent investigation, according to the comments on the release analysis According to the prior art can be done.

With It is thus the solution according to the invention possible to perform an advance screening, wherein here only small amounts of active ingredients in the composition samples required are. The proportion of sample material to be discarded is low due to the lower amounts per sample, which is why Method in addition to a considerable time savings in implementation the analysis procedure also by significantly lower costs characterized the known assessment method.

The inventors have recognized that it is contrary to common prejudices possible, the Freiset The reduction of the corresponding amount or the volume of the composition to be assessed in view of the corresponding reduction of the available release volume by a functional context, in particular partially Proportionality to the previously used in the art release devices considerably larger size is possible. The solution according to the invention also makes it possible to achieve material savings of up to 80% and greater over conventional methods. Another significant advantage in addition to the material savings is the possible increase in throughput due to the lower required experimental times. Furthermore, the solution according to the invention has the advantage that due to the smaller size, a simple disassembly and cleaning is possible.

Although are from the publications Debbie J. Crail, Adam Tunis, Richard Dansereau, "International Journal of Pharmaceutics, 269 (2004), 203-209 It is previously known to be able to reduce the release volumes in a corresponding manner in order to obtain the same values for the parameters which at least indirectly characterize the release behavior, as in devices with release volumes> 1000 ml, although here a reduction to the order of 200 ml is discussed. Also, this magnitude is not yet sufficiently adequate to reduce the time required for the composition sample evaluation and the costs of the required order of magnitude.

The Device according to the invention, which also as Screening device, that is device for pre-assessment properties of the compositions, in particular the release behavior in a release medium, includes one Receiving device for the single release volume and a drive unit associated with the means for mixing / distribution. Preferably, both can be attached to a frame or stored. This makes it possible to have a solid spatial Allocation between the release volume and the device for To create mixing / distribution. Further, means for supply the composition and / or means of removal after exposure to Device for acting on the composition present Sample and / or means for dosing the composition sample provided.

In terms of the arrangement and design of the individual release volume There are a number of possibilities. This can according to a first variant of directly in the central receiving device incorporated recesses are formed. In an advantageous Further development according to a second variant it is envisaged to form the single release volume from a release vessel, which can be arranged interchangeably in the receiving device. The release vessel is easily out of the receiving device to remove, whereby the addition of the composition sample and the trigger as well as the cleaning of the device are considerably simplified can. The assignment of the release vessel is through the association between receiving device and device defined for mixing / distributing. Furthermore, in a receiving device with the same holder and different dimensions Release vessels are used.

The single release volume is defined by a predefined geometric Form, in particular a three-dimensional cavity writable, wherein this one of the following forms or a combination from these corresponds: a cylinder, a cube, a cuboid, a cone, a truncated cone. To ensure the same Release conditions over the spatial Extension are the individual release volumes preferably with respect to a plane which by the in functional position Serving the receiving device perpendicular in the X and Z directions or Y and Z directions can be written symmetrically.

The in functional position characterizing the single release volume Dimensions are by a maximum height, d. H. Extension in Z-direction in the range between 2 mm and 250 mm, especially preferably 5 mm and 150 mm, most preferably 10 mm and 120 mm, while the maximum width, d. H. Extension in the horizontal direction in the range between 2 mm to 35 mm, more preferably 5 mm to 30 mm, most preferably 10 mm to 20 mm.

The means for mixing / distribution and / or the release volume are movable relative to each other. This is ensured by the mobility of the receiving device and / or the individual mixing / distribution device and / or a carrier for the mixing / distribution device. In this case, the release volume is preferably arranged stationary and the device for mixing / distribution against or within the release volume movable. The movement can take place in different directions. It is crucial that this is characterized by a functional position and a non-functional position, wherein the functional position is determined by the immersion of the device in the release volume.

The Movements of the device for mixing / distribution within of the release volume may be in horizontal and / or vertical direction. The movement can be oscillating or be made rotating. According to the chosen one Relative movement possibilities between the device for mixing / distribution and the release volume that can be assigned to it are appropriate storage and coupling options the individual device for mixing / distribution to a Provide drive. The drive can depend on the Choice of drive type either manually or via a prime mover respectively. In the former case, the single device with an actuator for driving at least indirectly coupled, wherein the actuating device is an operator is operable. This is either direct or via a transmission mechanism connected to the means for mixing / distribution. The actuation may vary depending on the design of the transmission mechanism between the actuator and the respective one Device for mixing / distribution, for example by pivoting or twisting done.

In an advantageous embodiment for warranty constant experimental conditions over a predefined one However, it is intended to use an engine, wherein the drive is preferably controllable. The controller can stepless or in stages. As drive units find Engines, in particular electric motors in the form of Gleich- or AC motors with adjustable speed use. Other Designs are also conceivable. The drive can be direct or via a transmission device for the purpose the speed / torque conversion between the drive and the individual Device for mixing / distributing and / or splitting the Performance to multiple mixing / distribution facilities be coupled with this. Versions with transmission facilities offer the advantage of optimal adaptation and overall smaller size.

The Device preferably comprises a plurality of release volumes, which can be equipped with compositions to be assessed, at the same time preferably under the same conditions different compositions to obtain experimental results. In this case, the device can be designed such that in each case a volume of release also means for mixing / distribution is assigned or a plurality of release volumes, that is, for example, a group of release volumes a device for acting on the obtained in this composition can be assigned together. This is especially the case when a Variety of release volumes are provided, not all used simultaneously and also different release volumes with the same facilities for mixing / distribution in operative connection to be brought.

Preferably be used for simultaneous release experiments a variety of release volumes are provided, each one assigned a separate device for mixing / distribution is. The release volumes and accordingly the facilities for Mixing / distribution can be in series next to each other be spaced apart. The arrangement is conceivable in one Row or a plurality of successively arranged rows, wherein the individual release volumes in parallel or between the individual rows are arranged to each other on offset.

A Use of a device for mixing / distribution in succession in several release volumes, for example, by the shift within and / or between the individual rows possible.

In A particularly advantageous further development is envisaged the arrangement of the individual release volumes at the receiving device to provide such that they are perpendicular to a functional position arranged to stand level axis are arranged. Particularly preferred chosen a circular arrangement, that is, the individual release volumes are on a common radius around said imaginary axis, which is preferably at rotationally symmetrical design of the receiving device the center axis corresponds, arranged. If the arrangement of the individual devices for mixing / distribution in analogue Way at a correspondingly executed, preferably circular or annular support, which also is characterized by a central axis, which is preferably aligned with the corresponding vertical axis of the receiving device It is possible, on the one hand, to collapse exact assignment of the individual facilities to the individual release volumes and further by rotation of the carrier for the individual facilities for mixing / distribution in the circumferential direction around the center axis of the carrier the assignment of the individual Device for mixing / distribution to the individual release volumes to change arbitrarily. This is particularly advantageous when the individual devices are firmly installed on the carrier and are not interchangeable.

The circular or annular arrangement offers the advantage that in the smallest space a variety of release volumes can be arranged are, wherein the entire device due to the respect Receiving device and the support device for the facilities very compact for acting on the compositions.

The Execution of mixing / distribution facilities in the release volumes can be variously. This is essentially dependent on the type of device for mixing / distribution and their mode of action. It can distinguished the facilities in terms of the type of movement be, with the corresponding movement through at least one horizontal or vertical movement or a combination of these characterizes is. The movement can be rotating or oscillating. The means for mixing / distribution preferably comprise a shaft which is characterized by a longitudinal axis is, wherein in one end region the coupling with the drive takes place, while in the opposite end of the arrangement of active elements. Preferably are on the outer circumference Stirrer provided. The Schafte dive either centrally or decentralized in the individual release volume. The central Arrangement is due to the immersion in the vertical direction extending symmetry plane characterized. The attachment to a corresponding support means is preferably detachable by force or positive connection, preferably plug-in connections, Bayonet or screw connections are chosen, the in a simple way allow safe removal and installation. The at the opposite end area, which in the release volume immersed, arranged active elements can be varied be executed. Preferably stirrers are used, the round, semicircular, rectangular or sickle-shaped stirrer blades with a maximum width in the range of 5 mm to 35 mm, preferably 10 mm to 30 mm, most preferably 15 mm to 20 mm and a maximum height of 3 mm to 35 mm, preferably 5 mmm to 25 mm, most preferably 6 mmm to 15 mm. Also conceivable are bar, armature, gate or propeller stirrers with similar dimensions. Glatt stirrers are preferred with a corresponding geometry in the above dimensions ranges used, but the lower width is smaller than the upper Width is. Upon rotation of the active elements about an axis, in particular Shaft axis, a stirring speed in the range between 5 rpm and 500 rpm, preferably 20 rpm to 250 rpm, especially preferably 50 U / min to 200 U / min selected. The stirring speed becomes in the case of so-called sample receptacles in the form of baskets chosen larger than those of so-called leaf stirrers.

In terms of the supply of the compositions to the individual release volumes, especially the composition samples, exist a variety of possibilities. The dosage may be before or during the supply take place. In the former case, the addition of the Composition sample in dosed form, while in the second case the device is characterized by a metering device, which is upstream of the feed opening and usually corresponds to the opening of the release vessel. In the simplest case, two staggered parallel arranged plates with corresponding receiving openings chosen for intake and dosage of substances directly are provided at the release openings. By a relative movement between the individual holes, the substance is metered into the release vessel.

The Means for removing the present after the action of the device Samples can also be made in different ways be. The removal can be done manually or automatically. In the simplest Case are corresponding removal openings and withdrawal channels provided in the receiving device.

through conventional cannulas or sample drawing angle a removal manually done from these channels. By Connection of appropriate suction, removal can also automated.

In a particularly advantageous embodiment, the means for removal in the mixing / distribution device, in particular integrated in the shaft, as this anyway during the immersion in the release volume with the composition sample and the Release medium comes into contact and thus a Deduction allows.

at Arrangements with several devices, in particular in the set forth circular arrangement of recording devices with accordingly circular release volume arranged around an axis and arrangements of devices for acting circular in one axis, preferably all individual facilities preceded by a common drive, wherein the power transmission via preferably a rotational speed / torque converter takes place, which in the simplest case as a simple transmission gear is designed. Preferably, the drive unit is a transfer case downstream, which allows a single or multi-level distribution, where each of the individual drives with the facilities for mixing / distribution are connected.

The solution according to the invention is followed Gend explained with reference to figures. It details the following:

1 clarifies the course of a two-stage method according to the invention for formulation determination on the basis of a signal flow diagram;

2 illustrates in schematic highly simplified representation of the basic structure of a device according to the invention for the pre-assessment of predefined properties, in particular preliminary assessment of solubility properties, in vitro properties and pre-assessment / prediction of in vivo properties of compositions;

3a to 3d exemplify arrangement variants for release volumes at reception facilities;

4a to 4f exemplify arrangement variants for facilities for mixing / distributing to carrying facilities;

5 shows a perspective view of a particularly advantageous embodiment of a device according to the invention;

6 illustrates an advantageous embodiment of a receiving device;

7 illustrates an advantageous integration of the means for sample extraction in the device for mixing / distribution;

8th illustrates an embodiment of a combined support and drive unit;

9 exemplifies an advantageous embodiment of a transfer device of a combined support and drive unit;

10 illustrates an example of an axial section, an embodiment of the means for metering.

The 1 illustrates by means of a Signalflußbildes the flow of a method according to the invention for finding suitable formulations by analyzing the solubility properties of both the in vitro properties and pre-assessment / prediction of in vivo properties of formulation proposals characterizing samples of compositions, hereinafter composition samples 3 , which are substances or mixtures of substances. Formulations are medicaments which are understood to be substances and / or preparations of substances intended for use on or in the human or animal body. These usually contain at least one active ingredient and optionally further excipients, which may be assigned different functions, for example a carrier function for the active substance or substances, the influencing of properties of the active ingredients and of the release behavior. The individual composition samples are characterized at least by an aggregate state and a size characterizing the amount of the composition. The amount can be in the solid state of the composition samples 3 For example, be characterized by a weight, dimensions or a volume. The composition of the individual sample itself is characterized by a substance or mixture of substances, wherein in substance mixtures a ratio characterizing the proportion of the individual substances is used to describe the composition. The compositions may be in various forms, solid, semi-solid, liquid or gaseous.

The process according to the invention has two stages and essentially comprises two process stages I and II which can be carried out independently of one another in terms of time and location. Depending on predefined desired setpoint values XE _, for solubility properties, both in vitro properties and preliminary assessment / prediction of in vivo properties E, but in particular for the release behavior, in a first method step I, an amount of MA to be taken into consideration is equal and same or different state of existing or in their composition and / or their state differing from each other samples of compositions or composition samples 3 and subjected to an analysis method V1, wherein based on the actual values XE _, a preselection of theoretically suitable compositions MVA from the initial quantity MA is made as analysis results. The amount MA of the composition samples 3 is through a number of composition samples 3 characterized by n3. The suitable compositions MVA determined after the preselection correspond to a subset of the initial amount MA. The preselection takes place as a function of the desired setpoint values XE _intended for desired predefined properties E, in particular solubility properties such as the release behavior in a release medium, taking into account a tolerance range T. The compositions MU considered to be unsuitable are no longer taken into consideration and the formulation proposals forming these are discarded. The individual composition samples 3 become part of a release volume 2 introduced into a release medium contained therein and distributed in this or mixed with this and / or only in response to the release medium released substances are distributed or with the release medium with the help of facilities 7 mixed for mixing / distribution. Here, a homogeneous distribution is sought. This is done in a device 1 for the preliminary assessment or screening of properties of compositions, in particular solubility properties, in particular the release behavior of medicaments, in-vitro properties and preliminary evaluation / prediction of in-vivo properties as shown in the following figures. The process is designed with regard to the procedure as in known methods for release analysis, but differs significantly in the size of the release volume provided 2 and the related amount of the composition of a composition sample 3 , The volume of release used 2 for the analysis method V1 in the first method step I in the range of> 0 ≤ 100 ml, preferably ≤ 50 ml, most preferably in the range between 5 ml and 30 ml inclusive. Accordingly, the size or amount of the individual composition sample 3 to the release volume 2 adapted and considerably reduced compared to conventional methods. The inventor has realized that prior to assessing the release behavior of compositions, it does not require large amounts of composition for a sample, but also reduces the release volume known from known apparatus 2 and facilities 7 comparable evaluation results for distribution and / or mixing to a predefined scale, which lie within a tolerance band compared to analysis values with conventional equipment operating with very large release volumes. As a result, with a significantly lower use of materials, a larger number of release analyzes can be carried out, the throughput of samples per unit of time can be considerably increased, and the apparatus 1 used for this purpose can be handled significantly more simply. This first method step I is used for the preliminary analysis and allows a reliable prediction of a tendency behavior and a secure preselection of suitable compositions MVA, for which in a second method step II the analysis results secured with conventional apparatus sizes and in terms of Accuracy are verifiable. Due to the reduced equipment, the release behavior in the first process step can be determined very quickly with a reliable prediction of the tendency, wherein the throughput of samples per unit time is also increased. Due to the material requirement required in this reduced release volume, larger quantities of samples can be assessed very inexpensively and taken into account in the formulation of a formulation. The compositions of the pre-selected samples MVA considered to be suitable are then tested for release behavior in a second process step II for scaling and concretization by subjecting the compositions of enlarged sample size corresponding to the preselected composition samples to a release process V2 in a greatly enlarged apparatus, and Further evaluation AS2 determined the finally considered suitable compositions ME or the compositions MVA be confirmed.

The 2 illustrates in schematic highly simplified representation of the basic structure and the basic design of an inventively running device 1 for the pre-assessment or screening of properties of compositions, in particular solubility properties such as the release behavior of drugs, in-vitro properties and pre-evaluation / prediction of in-vivo properties. By pre-assessment is meant a determination or determination of solubility properties within a predefined, preferably relatively narrow tolerance band (target profile of the release) compared to the actual actual value, which makes it possible to make a secure preselection. The device 1 for the pre-evaluation of properties comprises at least one release volume 2 for receiving a sample of the composition to be evaluated, in particular composition sample 3 , under which a mixture of substances or substances is understood. The release volume 2 corresponds at least partially by walls 6 bounded cavity, which preferably by a release vessel 4 which is suitable to a volume of the composition sample 3 , which is also called the composition volume 5 is called to record. The release volume 2 , in particular release vessel 4 is in a recording device 12 arranged. The 1 represents the functional position of the device 1 dar. The recording device 12 rests on a base surface, in particular a level surface. To clarify the individual directions is to the device 1 a coordinate system created. The support level for the receiving device 12 , which is formed by the base area, corresponds to the XY plane. Distances and distances in the vertical direction can be described via the Z coordinates. The orientation of the release volume 2 takes place in the illustrated case such that the opening 4.1 of the release vessel 4 pointing vertically upwards. The release volume 2 is described by a three-dimensional body and preferably designed symmetrically with respect to an axis A2 aligned perpendicular to the base surface. the opposite is the geometry of the composition volume 5 defined when introduced into the release medium depending on the state of aggregation, ie fixed or undefined, ie changeable. Depending on the state of matter lies the composition sample 3 in liquid, gaseous, semi-solid, especially pasty or solid form. The release volume 2 is greater than the composition volume 5 , To evaluate the release behavior, the composition sample 3 in the release volume 2 introduced into a release medium. The release vessel 4 thus takes in addition to the composition volume 5 also the corresponding fluid volume of the release medium. The individual release volume 2 is a facility 7 for mixing / distributing the composition sample to be evaluated 3 and / or the released components in the release volume 2 assigned. At this facility 7 it is usually a mechanical on the release medium and indirectly the composition sample 3 acting device comprising within the release volume 2 movable active elements 8th , The device 7 is at least in the functional state in the release volume 2 submersible. Preferably, the device is 7 in at least two positions 7-I and 7-II be brought. The first, not shown here position 7-I corresponds to the functional position in the immersion state, the second position shown 7-II corresponds to a position outside the release volume 2 , The movement within the release volume 2 can be oscillating, pivotable about a predefined axis or rotatable about an axis within the coordinate system. Preferably, the device is 7 for mixing / distribution in the release volume 2 as a stirring device 9 executed, which a shank 10 comprises, which is formed by an elongated structure, in particular cylindrical body and a first, in the release volume 2 submergible end area 10.1 and a second, at least indirectly with a drive 13 dockable end area 10.2 includes. The shaft axis A10 corresponds to the axis of symmetry of the shaft and is coaxial with the axis A2 of the release volume 2 or aligned parallel to this. The shaft 10 is rotatably mounted about the shaft axis A10, which is also referred to as a rotation axis. The shaft 10 indicates at the first, in the release volume 2 extendable end region 10.1 on the outer circumference 11 knitting elements 8th in the form of round, semicircular, rectangular, sickle-shaped or snail-like elements, in particular stirrer blades, paddles et c. The shaft axis A10 is central or decentralized with respect to the release volume provided depending on the geometry 2 arranged axis A2 arranged. Regarding the arrangement of the individual active elements 8th on the outer circumference 11 are distinguished axially, usually down or radially arranged active elements, which leads to the distinction between axially or radially conveying stirrers. The drive 13 can be done manually or automatically. This is for speed / torque conversion preferably via transmission elements / a transmission device 14 with the device 7 coupled. This is in the simplest case, a transmission. The device 7 is to a carrier 16 stored. This forms together with the drive 13 and the transmission elements / the transmission device 14 a combined drive and support unit 15 attached to a frame 17 is stored. Preferably, the receiving device is also 12 stationary on the frame 17 storable. Furthermore, depending on the design and timing sequential means 18 to the feed, means 19 for dosage and remedies 20 be provided for sample withdrawal. If the feed is done manually, the funds will be 19 formed by corresponding spatially separate funding, such as a transport spoon. The dosage may also already be outside the device 1 take place, for example, in a separate metering device, which is the case especially for solid samples, which are compressed from substances or mixtures of substances to tablets. The means 18 and 19 are therefore not a mandatory part of the device 1 but may also be partially or fully integrated with them. Furthermore, it is optionally conceivable for in-situ measurement, a measuring device 21 provide, which in the release volume 2 extends into it. The withdrawal of the samples after the experiments from the individual release volumes 2 either also manually, for example by means of a pipette or by appropriate means 20 attached to the device 1 can be provided.

According to the invention, this is the composition volume 5 receiving release volume 2 , in particular that descriptive release vessel 4 or the wall that bounds 6 the receiving device 12 integrated design designed and dimensioned such that this volume is in the range of> 0 ≤ 100 ml, preferably ≤ 50 ml, most preferably in the range between 5 ml and 30 ml inclusive. This makes it possible to pre-analyze small amounts of compositions and thus small amounts of starting in the range of 10-20% relative to a standard approach required in comparison with conventional analytical methods for the evaluation of a composition which serves as a formulation proposal for a formulation. The thus determined actual values XE _is used as described in 1 described as analysis results regarding the release behavior, in particular the solubility in another medium of the preliminary assessment for further experiments.

With regard to the specific embodiment of the device 1 There are a variety of options for prejudging properties. Preferably, devices are 1 which uses a plurality of release volumes 2.1 to 2.n to simultaneously prepare a variety of different composition samples in one analysis step 3 in terms of release under the action of different or identical devices 7 to judge for mixing / distribution. The individual release volumes 2.1 to 2.n are doing in a recording device 12 integrated or arranged. These can be from release vessels 4 be formed or integral with the receiving device 12 of arranged in this recesses. The 3a to 3d illustrate different arrangement options of the individual release volumes 2.1 to 2.n , The individual release volumes 2.1 to 2.n are in the following 3a to 3d exemplified executed with the same size. This also applies to these forming cavities, which can be described by three-dimensional geometric shapes or body. It is also conceivable, however, the case not shown here in terms of size and geometry executed release volumes 2.1 to 2.n in a recording device 12 ,

The 3a illustrates a first arrangement of the release volumes 2.1 to 2.n in two views, a top view and a greatly simplified axial section in which the individual release volumes 2.1 to 2.n in a row 22 are arranged to each other. The views refer to the coordinate system according to 2 , The view from above is characterized by a view on the XY plane, while the axial section depending on the arrangement in the XZ or YZ plane, in the illustrated case accordingly 2 in the XZ plane. The release volumes 2.1 to 2.n are spaced from each other next to each other, wherein the distances a between two juxtaposed release volumes are preferably chosen to be equal.

In contrast, illustrates the 3b an evolution according to 3a with a variety of release volumes 2.1 to 2.n in at least two rows offset in the Y direction 22.1 and 22.2 are arranged. Again, the arrangement is within the individual rows 22.1 to 22.2 preferably with the same distance a between two mutually adjacent release volumes 2.n and 2.n +1. The distances between the individual rows b can likewise be designed to be the same or with different dimensions in the case of a large number of rows arranged in series. In the illustrated case, the arrangement of the individual volumes between the individual rows takes place 22.1 and 22.2 parallel to each other. Also conceivable is an offset of the rows 22.1 and 22.2 in the X direction to each other, for example, by a / 2 in the X direction, as in the 3c played.

In a particularly advantageous further development according to 3d it is intended a variety of release volumes 2.1 to 2.n in a space-saving manner to arrange circularly about an axis A12. The recording device 12 is formed here by way of example of a circular support block and is characterized by a diameter D. The arrangement diameter of the release volumes 2.1 to 2.n is denoted by DA. The axis A12 is from a vertical to the support plane of the receiving device 12 formed and corresponds in the illustrated case the center axis or axis of symmetry of the support block. Shown here is an arrangement on a common diameter DA. However, it is also conceivable variant of the arrangement not shown here on several different diameters with or free of offset in the circumferential direction.

In a similar way to those in the 3a to 3d Arrangement possibilities of the individual release volumes illustrated by way of example 2.1 to 2.n the arrangement of the individual facilities takes place 7.1 to 7.n for mixing / distribution of the composition samples 3.1 to 3.n with those in the individual release volumes 2.1 to 2.n contained release media. For versions of the 3a to 3c is exemplary in 4a an arrangement of the individual facilities 7.1 to 7.n on a carrier 16 provided, which preferably part of a central support and drive unit 15 is. On the carrier 16 are the individual facilities 7.1 to 7.n with respect to the coordinates of the arrangement either stationary, but at least rotatable about an axis or pivotally driven or with respect to the arrangement coordinates in addition to the drive movement when immersed in the respective release volume 2.1 to 2.n and slidably stored within the release medium.

To clarify the individual directions is in the 4a and 4b also reproduced the position of the coordinate system, the view from above a view of the XY plane in functional position without representation of the drives 13 . 13.1 to 13.n and the view from the right is a view on the XZ plane, also without playback of the drives.

In the 4a is an example of a right view of the facilities 7.1 to 7.n for mixing / distribution in a view on the XZ plane. The individual facilities 7.1 to 7.n are spaced apart in the X direction is stationary, but at least drivable running. It can according to 4a each of the facilities 7.1 to 7.n a separate drive 13.1 to 13.n be assigned, with the individual drives 13.1 to 13.n independently or in groups or jointly controllable. In an advantageous development is according to 4b a central drive 13 intended. The distribution of the power to the individual facilities 7.1 to 7.n via transmission elements or a transmission device 14 in the form of a transfer case, wherein preferably the drive power evenly on all devices 7.1 to 7.n is split. In this case are drive 13 , Transmission device 14 and carriers 16 as a combined support and drive unit 15 executed. For optional decoupling of individual devices 7.1 to 7.n from the drive 13 not shown here switchable coupling devices in the connection of the individual device 7.1 to 7.n with the drive 13 to get integrated.

The facilities 7.1 to 7.n are in installation position by a extending in the Z direction shaft 10 characterized, here by way of example only for the device 7.n designated. This is in the end area 10.2 on the carrier 16 mounted, preferably rotatable about an axis A10 formed by the shaft axis. The shaft 10 also indicates his, from the carrier 16 groundbreaking end area 10.1 knitting elements 8th which are designed in a manner corresponding to stirrer as paddle or Rührerblätter and may have different geometries. The individual facilities 7.1 to 7.n are on the carrier 16 stored, in turn, on a frame 17 the device 1 in the vertical direction, is slidably mounted here by double arrow in the Z direction.

According to an advantageous development can according to 4c in a view from above the individual facilities 7.1 to 7.n in installation position with their drives not shown here 13.1 to 13.n be slidably mounted in the X direction, so that a unit of frame 17 and carriers 16 to different series arrangements of release volumes 2.1 to 2.n is customizable.

In an embodiment according to 4d which likewise shows a simplified view from above onto a support 16 without representation of the drives 13.1 to 13.n or a central drive 13 , as in 4b reproduced, clarified, can also the entire carrier in the Y direction on the frame 17 be slidably mounted. This embodiment is especially in assigning a single-row arrangement of the facilities 7.1 to 7.n on a carrier 16 to a recording device 12 with release volumes 2.1 to 2.n in several rows offset in the Y direction 22.1 to 22.n as exemplified in 3b reproduced, conceivable.

4e illustrates an embodiment with a plurality of rows arranged in the Y direction 23.1 and 23.2 of facilities 7.1 to 7.n for an embodiment of the receiving device 12 according to 3b , where the arrangement of the facilities 7.1 to 7.n in analogy to the arrangement of the release volumes 2.1 to 2.n in the receiving device 12 on the carrier 16 spaced from each other with a distance a within each row to each other and with a distance b between the rows 23.1 . 23.2 he follows. To adapt to a design according to 3c can the individual facilities 7.1 to 7.n according to the illustrated arrows within the rows 23.1 . 23.2 be moved in the X direction, with individual or all facilities 7.1 to 7.n slidable on the carrier 16 are stored.

The displacement possibilities of 4a to 4e are combined with each other, with the displaceability of the individual facilities 7.1 to 7.n to each other in versions with central drive 13 through the transmission device 14 limited or not possible. The connections of the individual facilities 7.1 to 7.n with the carrier 16 takes place positively or positively, in particular by plug or bayonet connections. Thereby, relative movements between the facilities 7.1 to 7.n and the carrier 16 already be integrated into the execution of the connections.

The 4f exemplifies a possibility of arranging individual devices 7.1 to 7.n for an arrangement of the release volumes 2.1 to 2.n according to 3d , The basic structure of the device 7.1 to 7.n corresponds to how, for the 2 and 4a described. Again, there is a carrier 16 provided, which is preferably designed as a symmetrical, in particular rotationally symmetrical component about an axis A16 and can be described by a diameter D16. The axis A16 is aligned in the installed position with the axis A12 of the receiving device 12 , The arrangement of the facilities 7.1 to 7.n takes place in accordance with the arrangement of the individual release volumes 2.1 to 2.n at the receiving device 12 also circular about the axis A12 aligned with the axis A16 on a diameter DA16, wherein on this diameter DA16 acting as axes of rotation shank axes A10 when executing the facilities 7.1 to 7.n as stirring devices 9.1 to 9.n. are arranged. These are coaxial or eccentric to the symmetry axes A2 of the individual release volumes 2.1 to 2.n can be arranged in functional position. Preferably, the individual devices 7.1 to 7.n also here detachable on the carrier 16 stored, in particular when equipped with different devices 7.1 to 7.n and / or different drive powers by different drives 13 and / or different translation facilities 14 and / or for the purpose of Swinging out, the carrier 16 at least about its axis A16 is rotatable and optionally additionally from its parallel position to the receiving device 12 is moved out, in particular - but not shown here - is pivotable.

Also not shown in the view is the displaceability of the carrier 16 in the Z direction.

In all in the 4a to 4f illustrated embodiments, the support and drive unit 15 also stationary on the frame 17 be stored, then only the facilities 7 displaceable relative to the carrier 16 are stored. Advantageously, the required relative movements between the individual device 7.1 to 7.n and the receiving device 12 However, about the sliding and / or pivoting of the carrier 16 at the frame 17 generated.

The in the 2d and 4f illustrated embodiments of the receiving device 12 for the release volumes 2.1 to 2.n and the central support and drive device 15 are in a particularly advantageous embodiment of a device 1 in 5 shown. This shows a central support and drive unit 15 with on a carrier 16 Circular about an axis A16, which is arranged in the functional position coaxial with the axis A12 of the receiving device, arranged means 7.1 to 7.n in the form of agitators 9.1 to 9.n. , These are about the storage on the carrier 16 and the vehicle 16 at the frame 17 in their position relative to one another and / or with respect to the receiving device 12 fixed. The recording device 12 is stationary on the frame 17 can be arranged, in particular fastened, wherein the connection is made by force or positive engagement and is preferably carried out detachable. The central support and drive unit 15 is opposite the receiving device 12 at least in the vertical, ie Z-direction slidably mounted on the frame. This is done by appropriate means in the connection between the support and drive unit 15 and the frame 17 realized. In the case shown, the support and drive unit 15 displaceable, for example on a sliding guide on the frame 17 stored, with the movement via a pivot lever 25 and a transmission mechanism 26 is produced. The determination can be made manually or via appropriate locking devices, for example in the form of locking or locking or clamping devices. The recording device 12 is in analogy to in 2d shown receiving device 12 educated. This comprises a support block 12.2 in which the release volumes 2.1 to 2.n are incorporated. The carrier block can be made heatable or unheated. In a particularly advantageous embodiment, the training is heated. The release volumes 2.1 to 2.n can thereby from in the receiving device 12 in corresponding recesses and holders can be introduced release vessels 4 be formed or recesses 24.1 to 24.n in the carrier block 12.2 itself. The design of the individual release vessels 4 may depend on the quantities of the individual composition samples to be assessed 3.1 to 3.n done variously.

In an alternative, not shown embodiment, the facilities 7.1 to 7.n formed of receptacles in the form of baskets or baskets. These are lattice-like elements with a fixed geometry in the form of a basket or variable geometry mesh, which on the carrier 16 are releasably attachable and the appropriate composition samples 3.1 to 3.n take up. These receptacles are in the release volumes 2.1 to 2.n insertable and relatively movable within these to these, for example, also via a drive 13 ,

The in the 5 illustrated embodiment provides a particularly compact design of a device 1 for the pre-evaluation of properties. This is due to a large number of release volumes 2.1 to 2.n characterized, which are arranged in a particularly space-saving manner to each other. Furthermore, this applies analogously to the positioning and the drive 13 the individual facilities 7.1 to 7.n , The drive 13 is designed as a central drive and transmission equipment 14 , preferably a transfer case with the individual devices 7.1 to 7.n connected.

The 6 illustrates in an axial section, the execution of a recording device 12 as stated in an embodiment according to 5 can be used. Recognizable are the release volumes 2.1 to 2.n forming recesses 24.1 to 24.n which are executed in the illustrated case in the form of cylindrical recesses. These extend in functional position of the receiving device 12 in the vertical direction, these are open-edged aligned with opening upwards. In the bottom area has the single recess 24.1 to 24.n viewed in cross section on a curved shape. In the recesses 24.1 to 24.n can do the composition samples 3.1 to 3.n and introducing the required release medium. Preferably, the receiving device 12 heatable. The heating can be direct or indirect. In the case shown, a heating medium is used, for example in the form of a fluid which determines the release volumes 2.1 to 2.n descriptive recesses 24.1 to 24.n especially in the area of their walls 6 lapped. Other designs are conceivable, preferably an embodiment is selected at which the individual channels provided for guiding the heating medium are arranged and aligned such that at all release volumes 2.1 to 2.n the same conditions prevail over their extension in the vertical direction. The choice of material for the recesses 24.1 to 24.n forming recording device 12 takes place in such a way that it is characterized by a corresponding heat transfer behavior in order to be in the range of the release volumes 2.1 to 2.n a corresponding heating of the release medium within it and the corresponding composition sample 3.1 to 3.n to enable. In the case shown is an annular heating channel 27 provided, which extends uniformly around the center axis A12. This is the recording device 12 in the illustrated case, preferably at least in two parts, comprising a core 12.1 and one the release volume 2 including and the support block 12.2 forming hood-shaped ring part. The ring member is designed such that this bell-shaped on the core part 12.1 under formation of the annular heating chamber 27 can be placed. The annular heating chamber 27 extends in the circumferential direction around the core 12.1 and in the vertical direction at least over a portion of the vertical extent of the individual release volumes 2.1 to 2.n in the vertical direction.

The supply of the annular heating chamber 27 with the heating medium, via appropriate feed channels 28 , wherein preferably to maintain uniform conditions over a predefined period of time, the heating medium via the feed channels 28 and discharge channels 29 can be performed in a circuit, preferably external to the receiving device 12 is performed, wherein in the external region, a heating of the heating medium, in particular fluid is made. This is the appropriate recording device 12 from the actual heating function almost self-sufficient. The control of the temperature can be outside the recording device 12 be made by heating the circuit in the externally guided circuit part. Conceivable, however, are other embodiments, for example, the receiving device 12 can be arranged on a hot plate or includes this.

The in the 6 illustrated embodiment for the receiving device 12 represents a particularly compact and advantageous embodiment.

The recording device 12 in the 5 assigned central support and drive unit 15 is exemplary in terms of an embodiment in the 8th represented by an axial section through this in a simplified representation. A recognizable in terms of the geometric shape of the receiving device 12 adapted carrier 16 which is formed by an annular or disc-shaped element and on which the individual devices 7.1 to 7.n for mixing / distribution of the composition samples 3.1 to 3.n or the released constituents are stored with the release medium during the release process. The storage is stationary with respect to the arrangement in the disk-shaped element, but the individual device 7.1 to 7.n is rotatably supported about its shaft axis A10. The device 7.1 to 7.n are in the case illustrated as stirring devices 9.1 to 9.n. formed, comprising substantially a stirrer shaft 10 and active elements arranged thereon 8th , which can be executed in different ways. A single institution 7 is exemplary in 7 shown. The shaft 10 is thereby by an end area 10.2 characterized, which is rotatably mounted on the disc-shaped element and via which preferably the drive takes place, while the other end portion 10.1 is executed wegerstreckend in installation position of the disc-shaped element.

Further, the carrier 16 , in particular the disc-shaped element preferably likewise rotatable about its center axis A16. This rotation makes it possible to use the individual facilities 7.1 to 7.n in a corresponding manner to the individual release volumes 2.1 to 2.n assigned.

The drive is via at least one drive unit 13 preferably such that all individual devices 7.1 to 7.n be driven at the same speed. The drive 13 is over at least one transmission device 14 , In particular speed / torque converter means in the form of a transfer case 31 each with the individual facilities 7.1 to 7.n connected. About this is the over the drive 13 introduced drive power to the individual devices 7.1 to 7.n is split. In a particularly advantageous manner, a uniform distribution takes place. Other versions are conceivable. An example of such a speed / torque converter is shown in FIG 9 based on a section of the central support and drive device 14 played. The speed / torque converter comprises in the illustrated case a plurality of gear stages, each coupled to a central drive gear R1. The drive pinion R1 is in a circular arrangement preferably in the region of the center axis A16 of the central support and drive unit 15 rotatably mounted and meshes respectively with transmission gears of the transfer case 31 , which in turn power each on two more output gears 32.1 to 32.n transferred, each with the individual facilities 7.1 to 7.n are connected.

As a drive 13 appropriately designed DC or AC motors with adjustable speed use. Other versions are also conceivable. The speed of each stirring device 9.1 to 9.n. is chosen in the range between 50 U / min and 200 U / min, more preferably 50 U / min to 150 U / min. In this case, rotational speeds in the range between 50 U / min and 100 U / min are preferably used for smooth stirrers, so-called paddles, and 100 U / min to 150 U / min with sample receptacles in the form of baskets, in particular receiving trays. The sample receptacles are bodies into which the substances can be introduced to move in the release medium. Such baskets can analogously to the stirring devices on the shaft 10 and / or the carrying device 16 be attached. They consist partly or completely of wire nets / meshes with a mesh size in the range of 0.1 mm to 1 mm, preferably 0.2 mm to 0.8 mm, most preferably 0.3 mm to 0.5 mm.

The release volumes 2.1 to 2.n can be performed in various ways. These may, but not shown here, be designed with a cylindrical cross section, cubic cross section, with a cuboidal cross section, a conical or truncated cone-shaped cross section. The arrangement takes place in functional position when used in the device 1 for the pre-evaluation of properties, wherein the extension in the Z-direction is the maximum height in the range between 2 mm to 250 mm, preferably 5 mm to 150 mm, most preferably 10 mm to 120 mm, while the extension in the width direction in the range between 2 mm to 35 mm, particularly preferably 5 mm to 30 mm, very particularly preferably 10 mm to 20 mm.

As facilities 7 so-called stirring or sample receptacles are used, which are movable in the release volume relative to this and achieve an effect by the movement. One possible such stirrer form is exemplified in US Pat 7 played. In this case, round, semicircular, rectangular or sickle-shaped stirrer having a maximum width in the range of 5 mm to 35 mm, more preferably 10 mm to 30 mm, most preferably 15 mm to 20 mm and a maximum extent in the vertical direction of 3 mm 35 mm, particularly preferably 5 mm to 25 mm, very particularly preferably 6 mm to 15 mm or beam, anchor, gate or propeller stirrer with similar dimensions are used. In a particularly advantageous manner, plain stirrers are used whose height in the range of 3.84 mm, the lower width is 8.2 mm and the upper width is 18.6 mm.

The addition of the compositions to be evaluated 3.1 to 3.n to the individual release volumes 2.1 to 2.n can be done in different ways. The feeder can be made manually or semi-automatically. In a corresponding manner, the corresponding supply openings are arranged. Preferably, the supply openings are as in the embodiment according to 4 provided in the vertical direction directed upward. The semiautomatic addition of the samples in the form of the compositions takes place, for example, via a slide device which corresponds to the release opening of the release volumes. In the simplest case, this will be two offset plates 34.1 and 34.2 with holes 33.1 and 33.2 for taking up substances and dosing them either directly on the release vessels 4 or the Probenzugabeöffnungen the drive plate mounted. By moving the plates 34.1 . 34.2 against each other, the holes are superimposed and the substances in the release volumes 2.1 to 2.n , in particular release vessels 4 dosed. Otherwise, the feed can be made directly manually pre-dosed.

The sampling can not be shown here in detail laterally below the drive plate or by oblique holes through the drive plate. The removal can be done manually by means of conventional cannulas or sample drawing angle. In a particularly advantageous embodiment, the sampling takes place as in the 7 represented by the shaft 10 the device 7 and then in the area of the carrier 16 subtracted from. For this purpose, this is hollow and preferably coupled with a trigger device, which applies by way of example a negative pressure, thereby allowing a trigger.

In a further development can also separate feed and Extraction lines are provided, which serve the withdrawal of the samples.

The in the 4 ff. illustrated embodiments represent particularly advantageous embodiments. However, the solution according to the invention is not limited to these. It is crucial that the execution of the screening device according to the invention is characterized in that here in small available release volumes 2.1 to 2.n smallest amounts of samples, in particular composition volumes can be examined for their release behavior, the results obtained form the basis for more extensive experiments. This prescreening or pre-assessment allows a decided preselection and avoids unnecessary attempts and unnecessary use of materials.

1

contraption

2, 2.1-2.n

release volume

3, 3.1-3.n

composition sample

4

Release container release vessel

4.1

opening

5

constituent volume

6

wall

7, 7.1-7.n

Facility for mixing / distribution

7-I

first position

7-II

second position

8th

active element

9

agitator

10

shaft

10.1, 10.2

end

11

outer periphery

12

recording device

12.1

core

12.2

bell part

13

drive

14

transmission elements

15

central Carrying and drive device

16

carrier

17

frame

18

medium to the feed

19

medium for dosage

20

medium for sample withdrawal

21

measuring device

22 22.1, 22.2

line

23 23.1, 23.2

line

24.1-24.n

recess

25

pivoting lever

26

transmission mechanism

27

annular heating chamber

28

supply channel

29

drain channel

31

Transfer Case

32.1-32.n

Output gears

33.1, 33.2

drilling

34.1, 34.2

plates

A2

axis of symmetry release volume

A10

Axis, shaft axis

A12

Axis, Center axis of the receiving device

A16

Axis, Center axis of the vehicle

a

distance in X direction

b

distance in the Y direction

D

diameter the receiving device

THERE

Arrangement diameter the release volumes

D16

diameter of the carrier

DA16

Arrangement diameter of the devices 7

AS1, AS2

Evaluation / analysis

MA

amount the composition samples

MAV

amount theoretically suitable compositions

ME

amount suitable compositions

MU

amount unsuitable compositions

V1, V2

release process

R1

pinion

T

tolerance

X, Y Z

coordinates

e

properties

XE _should

setpoint

XE _is

actual value

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• US 5639974 [0006]
• - US 6558957 B1 [0006]
• US 6174497 B1 [0006]
• US 3572648 [0007]
• EP 0779506 [0008]
• US 6558957 [0009]
• WO 01/55698 [0009]
• - US 6174497 [0009]
• US 4879917 [0010]
• - US 6060024 [0011]

Cited non-patent literature

• Debbie J. Crail, Adam Tunis, Richard Dansereau: "Is the use of a 200 ml container suitable for dissolution of low dose drug products?", ", International Journal of Pharmaceutics, 269 (2004), 203-209 [0024]

Claims (47)

Contraption ( 1 ) for evaluating properties of compositions, in particular a screening device for assessing solubility properties, in vitro properties and pre-evaluating / predicting in vivo properties (E) of compositions comprising at least one, a composition sample ( 3 ) and release medium receiving release volume ( 2 . 2.1 - 2.n ) and at least one, the respective release volume ( 2 . 2.1 - 2.n ) associated device ( 7 . 7.1 - 7.n ) for distribution / mixing within the release volume ( 2 . 2.1 - 2.n ), characterized in that the size of the single release volume ( 2 . 2.1 - 2.n ) in the range of> 0 ml ≤ 100 ml, preferably between 5 ml and 50 ml, more preferably between 5 ml and 30 ml, most preferably between 5 ml and 20 ml, and the device ( 7 . 7.1 - 7.n ) for mixing / distribution within the release volume ( 2 . 2.1 - 2.n ) is designed and dimensioned such that it is suitable in the release volume ( 2 . 2.1 - 2.n ) to be immersed. Contraption ( 1 ) according to claim 1, characterized in that it comprises a receiving device ( 12 ) for the individual release volume ( 2 . 2.1 - 2.n ) and one of the institutions ( 7 . 7.1 - 7.n ) for mixing / distribution within the release volume ( 2 . 2.1 - 2.n ) associated drive unit ( 13 . 13.1 - 13.n ). Contraption ( 1 ) according to claim 1 or 2, characterized in that these means ( 18 ) for supplying the composition sample ( 3 . 3.1 - 3.n ) and / or means ( 20 ) for removal of the sample present after exposure to the device. Contraption ( 1 ) according to claim 3, characterized in that these means ( 19 ) for dosing the composition sample ( 3 . 3.1 - 3.n ). Contraption ( 1 ) according to one of claims 3 or 4, characterized in that the means ( 18 ) for supplying the composition sample ( 3 . 3.1 - 3.n ) and / or means ( 20 ) for the removal of the sample and / or means ( 19 ) for dosing the composition sample ( 3 . 3.1 - 3.n ) are formed by an integral unit. Contraption ( 1 ) according to claim 4 or 5, characterized in that the means ( 19 ) for dosing the composition sample ( 3 . 3.1 - 3.n ) comprises a variable metering slide device adapted to the individual volume of release ( 2 . 2.1 - 2.n ) is arranged upstream. Contraption ( 1 ) according to any one of claims 2 to 6, characterized in that the single release volume ( 2 . 2.1 - 2.n ) from directly in the central receiving device ( 12 ) incorporated recesses ( 24 . 24.1 - 24.n ) is formed. Contraption ( 1 ) according to any one of claims 2 to 6, characterized in that the single release volume ( 2 . 2.1 - 2.n ) from a release vessel ( 4 ) is formed, that in the receiving device ( 12 ) can be arranged interchangeably. Contraption ( 1 ) according to one of claims 1 to 8, characterized in that the release volume ( 2 . 2.1 - 2.n ) is formed by a three-dimensional cavity predefined geometric shape, which corresponds to one of the following geometries or a combination of these: - cylinder - cube - cuboid - cone - truncated cone Contraption ( 1 ) according to claim 9, characterized in that the release volume ( 2 . 2.1 - 2.n ) characterizing dimensions in the installed position by a maximum extent in the vertical direction in the range between 2 mm and 250 mm, more preferably 5 mm and 150 mm, most preferably 10 mm and 120 mm and a maximum extent in the horizontal direction in the range between 2 mm 35 mm, more preferably 5 mm to 30 mm, most preferably 10 mm to 20 mm are writable. Contraption ( 1 ) according to one of claims 1 to 10, characterized in that the device ( 7 . 7.1 - 7.n ) for mixing / distribution and / or the individual release volume ( 2 . 2.1 - 2.n ) are movable relative to each other. Contraption ( 1 ) according to claim 11, characterized in that the device ( 7 . 7.1 - 7.n ) for mixing / distribution in functional position within the individual release volume ( 2 . 2.2 - 2.n ) is movable in the vertical and / or horizontal direction. Device according to claim 11 or 12, characterized in that the device ( 7 . 7.1 - 7.n ) for mixing / distribution in functional position within the individual release volume ( 2 . 2.2 - 2.n ) is oscillatably movable. Device according to claims 11 to 13, characterized in that the device ( 7 . 7.1 - 7.n ) for mixing / distribution in functional position within the single release volume ( 2 . 2.2 - 2.n ) is rotatably movable. Contraption ( 1 ) according to one of claims 11 to 14, characterized in that the relative movement of the device ( 7 . 7.1 - 7.n ) for mixing / distribution in functional position within the individual release volume ( 2 . 2.2 - 2.n ) is controllable. Contraption ( 1 ) according to one of claims 2 to 15, characterized in that a plurality of spatially separated from each other arranged separate release volumes ( 2 . 2.1 - 2.n ) and each individual release volume ( 2 . 2.1 - 2.n ) An institution ( 7 . 7.1 - 7.n ) for mixing / distribution in functional position within the individual release volume ( 2 . 2.2 - 2.n ) assigned. Contraption ( 1 ) according to one of claims 2 to 16, characterized in that a plurality of spatially separated from each other arranged separate release volumes ( 2 . 2.1 - 2.n ) and a group of release volumes ( 2 . 2.1 - 2.n ) An institution ( 7 . 7.1 - 7.n ) for mixing / distribution in functional position within the individual release volume ( 2 . 2.2 - 2.n ) is assigned together. Contraption ( 1 ) according to claim 17, that the device assigned to a group ( 7 . 7.1 - 7.n ) for mixing / distribution within the single release volume ( 2 . 2.2 - 2.n ) between the individual release volumes ( 2 . 2.1 - 2.n ) of the group is movable. Contraption ( 1 ) according to one of claims 16 to 18, characterized in that the individual release volumes ( 2 . 2.1 - 2.n ) in at least one row ( 22.1 . 22.2 . 23.1 . 23.2 ) are arranged next to and / or behind one another. Contraption ( 1 ) according to claim 19, characterized in that the individual release volumes ( 2 . 2.1 - 2.n ) in the rows ( 23.1 . 23.2 ) are arranged offset from each other. Contraption ( 1 ) according to one of claims 16 to 20, characterized in that the individual release volumes ( 2 . 2.1 - 2.n ) in the receiving device ( 12 ) in a mounting position of the receiving device ( 12 ) aligned in the vertical direction axis (A12), preferably center axis of the receiving device ( 12 ) are arranged in the circumferential direction. Contraption ( 1 ) according to claim 21, characterized in that the individual release volumes ( 2 . 2.1 - 2.n ) are arranged in a circle around the axis (A12). Contraption ( 1 ) according to one of claims 16 to 22, characterized in that the individual release volumes ( 2 . 2.1 - 2.n ) are designed and dimensioned such that they are the same in terms of their geometric shape and / or dimensions. Contraption ( 1 ) according to one of claims 16 to 22, characterized in that the individual release volumes ( 2 . 2.1 - 2.n ) are designed and dimensioned such that they are designed differently with respect to their geometric shape and / or dimensions. Device according to one of claims 16 to 24, characterized in that the distance (a, b) between two mutually adjacent release volumes ( 2 . 2.1 - 2.n ) Is executed the same in at least one direction and / or circumferential direction. Device according to one of claims 16 to 24, characterized in that the distance (a, b) between two mutually adjacent release volumes ( 2 . 2.1 - 2.n ) is executed differently in at least one direction and / or circumferential direction. Contraption ( 1 ) according to one of claims 1 to 26, characterized in that the individual release volume ( 2 . 2.1 - 2.n ) is arranged symmetrically with respect to a vertical axis (A2) in the installed position in the receiving device and the device ( 7 . 7.1 - 7.n ) for mixing / distribution decentralized with respect to the axis (A2) can be arranged. Contraption ( 1 ) according to one of claims 1 to 26, characterized in that the individual release volume ( 2 . 2.1 - 2.n ) is arranged symmetrically with respect to a vertical axis (A2) in the installed position in the receiving device and the device ( 7 . 7.1 - 7.n ) for mixing / distribution centrally, in particular coaxially with respect to the axis (A2) can be arranged. Contraption ( 1 ) according to one of claims 1 to 28, characterized in that the individual device ( 7 . 7.1 - 7.n ) for mixing / distribution of active elements rotatable about an axis (A10) ( 8th ), in particular stirrer blades and / or paddles is formed. Contraption ( 1 ) according to claim 29, characterized in that the active elements ( 8th ) with a maximum extension in the width direction in the range of 5 mm to 35 mm, particularly preferably 10 mm to 30 mm, very particularly preferably 15 mm to 20 mm and a maximum extent in height or vertical direction of 3 mm to 35 mm, especially preferably 5 mm to 25 mm, most preferably 6 mm to 15 mm are executed. Contraption ( 1 ) according to one of claims 1 to 28, characterized in that the individual device ( 7 . 7.1 - 7.n ) for mixing / distributing a recording basket rotatable about an axis for receiving the composition samples ( 3 . 3.1 - 3.n ) is formed. Contraption ( 1 ) according to one of claims 29 to 31, characterized in that the individual device ( 7 . 7.1 - 7.n ) for mixing / distribution and / or constituents thereof, in particular the active elements ( 8th ) are interchangeable. Contraption ( 1 ) according to one of claims 29 to 32, characterized in that the individual device ( 7 . 7.1 - 7.n ) for mixing / distribution on a carrier ( 16 ) and / or the active elements ( 8th ) on a shaft ( 10 ) are releasably attachable. Contraption ( 1 ) according to claim 33, characterized in that the releasable connection is non-positive or positive fit, in particular as a plug or bayonet connection. Contraption ( 1 ) according to one of claims 29 to 34, characterized in that the individual device ( 7 . 7.1 - 7.n ) for mixing / distribution on a carrier ( 16 ) is rotatably mounted. Contraption ( 1 ) according to one of claims 29 to 34, characterized in that the individual device ( 7 . 7.1 - 7.n ) for mixing / distribution on a carrier ( 16 ) is slidably mounted. Contraption ( 1 ) according to one of claims 29 to 36, characterized in that the carrier ( 16 ) relative to the receiving device ( 12 ) is slidably mounted. Contraption ( 1 ) according to one of claims 29 to 37, characterized in that the individual devices ( 7 . 7.1 - 7.n ) for mixing / distribution in at least one row ( 23.1 . 23.2 ) are arranged next to and / or behind one another. Contraption ( 1 ) according to one of claims 29 to 37, characterized in that the individual devices ( 7 . 7.1 - 7.n ) for mixing / distribution around an installation position of the receiving device ( 12 ) aligned in the vertical direction axis (A16) on the support device ( 16 ), preferably center axis are arranged in the circumferential direction. Contraption ( 1 ) according to one of claims 2 to 39, characterized in that the individual devices ( 7 . 7.1 - 7.n ) for mixing / distribution a central drive ( 13 ) assigned via transmission elements or a transmission device ( 14 ) with the facilities ( 7 . 7.1 - 7.n ) can be coupled. Contraption ( 1 ) according to claim 40, characterized in that the transmission elements or transmission device ( 14 ) a transfer case ( 31 ) and, optionally, each of the facilities ( 7 . 7.1 - 7.n ) a switchable coupling device for coupling / decoupling from the drive ( 13 ) assigned. Contraption ( 1 ) according to one of claims 2 to 41, characterized in that the receiving device ( 12 ) is formed heated. Contraption ( 1 ) according to claim 42, characterized in that the receiving device ( 12 ) at least one fillable with a heating medium heating channel ( 27 ) and a feed and a drain channel ( 28 . 29 ) for the heating medium to form a circuit. Contraption ( 1 ) according to claim 42, characterized in that a heating source is arranged in or on the receiving device. Contraption ( 1 ) according to one of claims 3 to 44, characterized in that the means ( 20 ) for taking a sample in the receiving device ( 12 ) into the release volumes ( 2 . 2.1 - 2.n ), or a peel-off angle. Formulation process by analyzing the release behavior of samples of compositions ( 3 . 3.1 - 3.n ) characterized by the following features: In a first method step (I) specification of at least one setpoint value (XE _soll ) of at least one predefined property, in particular solubility property (target profile (E)) of a composition; Performing release experiments (V1) with samples of compositions ( 3 . 3.1 - 3.n ) in predefined release volumes containing release media ( 2 . 2.1 - 2.n ) having a size in the range of> 0 ml ≤ 100 ml, preferably between 5 ml and 50 ml, more preferably between 5 ml and 30 ml, most preferably between 5 ml and 20 ml, determining actual values of the predefined properties of Compositions, wherein the amount / size of the individual composition sample ( 3 . 3.1 - 3.n ) as a function of the respectively available release volume ( 2 . 2.1 - 2.n ) is selected; - Classification of the samples of the compositions ( 3 . 3.1 - 3.n ) depending on the actual values (XE _is ) as "possible suitable compositions" (MVA) or rejection as "unsuitable compositions"(MU); and in a second process step (II) - carrying out release experiments (V2) with Samples of compositions classified as "possible suitable compositions" (MVA) in release media containing size ranging in size from> 200 ml to 5000 ml, preferably 200 ml to 2000 ml, more preferably between 500 ml and 1000 ml, determining the actual values of predefined properties; Determination (AS2) of the suitable compositions as a formulation as a function of the actual values. A method according to claim 46, characterized in that in the first method step (I) at the same time a plurality of different samples of compositions ( 3 . 3.1 - 3.n ) to be analyzed.